There are significant differences in the response phenotypes of various mouse strains in two models of behavioral despair, the forced swim and tail suspension tests. In both tests, mice cease to try to escape from an adverse situation, exhibiting increased immobility. Both tests have high value for predicting the therapeutic activities of antidepressant medications. We will study recombinant inbred (Rl) mice derived from parental mouse lines that differ in their immobility responses in despair tests and in their responses to antidepressants. The immobility data from the two tests in the presence or absence of medication will be correlated with the high-density haplotype data available online to identify chromosomal regions that harbor genes that contribute to the immobility phenotype: so-called Quantitative Trait Loci (QTLs). We will be especially interested in gender-specific QTLs because of the increased risk for depression among the female population. mRNA isolated from brain regions will be profiled to measure the relative concentrations of each mRNA. mRNAs that exhibit differences in concentrations between the two parental mice, are coinherited with each QTL, and which derive from the QTL chromosomal interval will be identified. Their products represent candidate despair-modifying proteins. Transgenic mice that either increase or decrease the expression of each candidate mRNA will be generated to verify that the quantitative behavioral trait is determined by the activity of the product of that candidate gene. The identities of the genes responsible for the QTs offer a powerful point of departure for the development of new pharmaceuticals to treat depression.